In the United States, cardiovascular disease is the leading cause of death. Our research investigates how cells are recruited to the sites of heart and blood vessel injury and contribute to the progression of disease and influence recovery.
Our goal to determine the mechanisms by which plasminogen (Plg) regulates leukocyte migration and, thereby, the inflammatory responses that contribute to thrombosis and cardiovascular diseases. Our results suggest that leukocyte recruitment to sites of inflammation is dependent on Plg activation of metalloproteinase-9, a matrix degrading enzyme. Lp(a) is an independent risk factor for cardiovascular diseases, but the mechanism of its proarteriothrombotic role is not known. Lp(a) contains an LDL core plus apolipoprotein(a), that mimics the functions of Plg. In mouse models of inflammation we found apo(a) reduces neutrophil recruitment, independent of Plg, and reduces macrophage recruitment by inhibiting Plg. In addition to leukocytes, Plg also regulates stem cell recruitment, important for recovery of a myocardial infaraction.
Recently, we demonstrated a novel pathway induced by G-CSF of Plg-dependent stem cell mobilization from the bone marrow that requires MMP-9 activation and regulation of the SDF-1/CXCR-4 pathway and that this Plg-dependent pathway is important for cardiac repair after an MI.
Strategies to prevent thrombosis have lagged far behind due, in part, to the contribution of multiple and as yet undefined genetic factors that lead to thrombotic risk. In a region on mouse chromosome 17 that is homologous to a region in humans, we identified a candidate gene, EMILIN2, as a thrombosis modifier. EMILIN2, an extracellular matrix protein, is expressed in bone marrow and platelets and plays a role in the platelet function.
Sha J, McCullough B, Hart E, Shchurin A, Nassir F, Davidson NO, Hoover-Plow J. Apo(a) promotes thrombosis in plasminogen deficient mice in a vascular injury model. J Thromb Haemost 3:2281–2289, 2005 [PMID 16150044].
Hoover-Plow J, Shchurin A, Hart E, Gong Y, Schneeman T, Sha J. A physiological function for apolipoprotein(a): A natural regulator of the inflammatory response. Exp Biol Med 234:28–34, 2009. [PMID: 18997104]
Sa Q, Hart E, Nadeau JH, Hoover-Plow JL. Mouse chromosome 17 candidate modifier genes for thrombosis. Mamm Genome, 21:337-349, 2010. [PMID: 20700597].
Sa Q, Hoover-Plow J. EMILIN2 (Elastin Microfibril Interface Located Protein), potential modifier of thrombosis. Thromb J 9:9, 2011. [PMID: 21569335]
Gong, Y., Hart, E., Shchurin, A., Hoover-Plow, J. Inflammatory macrophage migration requires MMP-9activation by plasminogen in mice. J Clin Invest 118: 3012-3024, 2008. [PMID: 18677407]